Marsilje, Thomas, Stutz, Stefan, Boos, Andreas, Niklaus, Michel, Chen, Bei, Jiang, Songchun, Furet, Pascal, Mccarthy, Clive, Stauffer, Frederic, Guagnano, Vito, Vaupel, Andrea, Michellys, Pierre, Schnell, Christian, Jeay, Sebastien and Lu, Wenshuo (2016) Optimisation of a 5-[3-phenyl-(2-cyclic-ether)-methyl-ether]-4-aminopyrrolopyrimidine series of IGF-1R inhibitors. Bioorganic and Medicinal Chemistry Letters, 26 (8). pp. 2057-2064. ISSN 0960-894X

Abstract

Taking the pyrrolopyrimidine derived IGF-1R inhibitor NVP-AEW541 as the starting point, the benzyl ether back-pocket binding moiety was replaced with a series of 2-cyclic ether methyl ethers leading to the identification of novel achiral [2.2.1]-bicyclic ether methyl ether containing analogues with improved IGF-1R activities and kinase selectivities. Further exploration of the series, including a fluorine scan of the 5-phenyl substituent, and optimisation of the sugar-pocket binding moiety identified compound 41 containing (S)-2-tetrahydrofuran methyl ether 6-fluorophenyl ether back-pocket, and cis-N-Ac-Pip sugar-pocket binding groups. Compound 41 showed improved selectivity and pharmacokinetics compared to NVP-AEW541, and produced comparable in vivo efficacy to linsitinib in inhibiting the growth of an IGF-1R dependent tumor xenograft model in the mouse.

Item Type:	Article
Keywords:	Oncology, kinase inhibitor, insulin-like growth factor receptor-1
Date Deposited:	04 Oct 2016 00:45
Last Modified:	04 Oct 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28054